Purpose: Positron emission tomography (PET) ligands exhibit different levels of non-displaceable binding in vivo. In the case of ligands for the 18 kDa translocator protein (TSPO), the component of non-displaceable binding for the most widely used radiotracer, [11C]-(R)-PK11195, is relatively high compared to that for newer TSPO ligands. Non-displaceable binding is not often quantified in humans in vivo, partially due to a lack of available ligands that are known to be safe with which to displace binding to the target receptor. Recently, however, a technique has been developed to quantify the non-displaceable binding of TSPO tracers in vivo, by blocking the receptor with the TSPO ligand XBD173 and comparing the total volume of distribution ( ) pre and post-blockade. Here, we used an occupancy plot to quantify the non-displaceable binding ( ) of the TSPO PET tracers [18F]GE-180 and [11C]PBR28 in cohorts of people with multiple sclerosis (MS). We also compared plots of subjects carrying both high and mixed binding affinity polymorphisms of TSPO to estimate while potentially avoiding the need for receptor blockade.
Procedures: Twelve people with multiple sclerosis (MS) and high (HAB) or mixed (MAB) affinity binding for TSPO underwent baseline MRI and 90-minute dynamic [18F]GE-180 PET (n=6; 3 HAB and 3 MAB) or [11C]PBR28 PET (n=6; 3 HAB, 3 MAB). Either one week later ([18F]GE-180) or the same afternoon ([11C]PBR28), participants had repeat PET following a 90mg dose of XBD173. PET images were co-registered with T1 MR volumetric images and regions of interest (ROIs) were defined using the 83-region Hammers atlas. Arterial blood sampling was used to generate plasma input functions for the two-tissue compartment model to quantify . The non-displaceable fraction of the total volume of distribution ( ) was calculated using two independent methods: the occupancy plot (by modelling the differences in signal post XBD173), and the polymorphism plot (by modelling the differences in signal across presence and absence of rs6971 genotypes).
Results: Whole brain (mean ± standard deviation) was 0.29±0.17 ml.cm-3 for [18F]GE-180 and 5.01±1.88 ml.cm-3 for [11C]PBR28. for [18F]GE-180 was 0.11 ml.cm-3 (95% CI: 0.02, 0.16) using the constrained occupancy plot and 0.20 ml.cm-3 (0.16, 0.34) using the polymorphism plot. accounted for, on average, 55% of in the whole brain. Equivalent values for [11C]PBR28 were 3.81 ml.cm-3 (3.02, 4.21) and 3.49 (1.38, 4.27), with accounting for 67% of average whole brain .
Conclusions: Although the of [18F]GE-180 is low, indicating low brain penetration, half of the signal shown by MS subjects reflected specific TSPO binding. The of [11C]PBR28 was higher and two thirds of the binding was non-specific. No brain ROIs were devoid of specific signal, further confirming that true reference tissue approaches are potentially problematic for estimates of TSPO levels.